Methods of treatment using a gastric retained gabapentin dosage form

ABSTRACT

A method of treatment for epilepsy and other disease states is described, which comprises delivery of gabapentin in a gastric retained dosage form.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation U.S. Ser. No. 13/943,500, filed Jul.16, 2013, now allowed, which is a divisional of U.S. Ser. No.13/301,602, filed Nov. 21, 2011, now U.S. Pat. No. 8,529,955, which is acontinuation of U.S. Ser. No. 13/270,126, filed Oct. 10, 2011, now U.S.Pat. No. 8,440,232, which is a divisional of U.S. Ser. No. 12/563,781,filed Sep. 21, 2009, now U.S. Pat. No. 8,119,166, which is a divisionalof U.S. Ser. No. 10/903,879 filed Jul. 30, 2004, now U.S. Pat. No.7,612,112, which is a continuation-in-part of U.S. Ser. No. 10/280,309filed on Oct. 25, 2002, now U.S. Pat. No. 7,438,927, which claimspriority under 35 U.S.C. §119(e)(1) to U.S. Provisional Application Ser.No. 60/335,248 filed Oct. 25, 2001, the disclosures of which are allincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the use of gabapentin in a gastricretained dosage form. More specifically, the invention relates to theuse of such dosage form to treat epilepsy and other disease states.

BACKGROUND OF THE INVENTION

Gabapentin (1-(aminomethyl)cyclohexane acetic acid) is an anti-epilepticdrug that is currently available in 100 mg, 300 mg and 400 mg hard shellcapsule as well as 600 mg and 800 mg tablet dosage forms, withrecommended dosing of 900 mg to 1800 mg total daily dose in threedivided dosages. The oral bioavailability is dose-dependent, withapproximately 60% bioavailability for a dose in the range of 300-400 mg,but with only 35% bioavailability for a dose of 1600 mg (Bourgeois,Epilepsia 36 (Suppl. 5):S1-S7 (1995); Gram, Epilepsia 37 (Suppl.6):S12-S16 (1996)). The decrease in bioavailability with dose has beenattributed to carrier-mediated absorption (Stewart, et al.,Pharmaceutical Research 10(2):276-281 (1993).

In early work with rats, Vollmer, et al., Arzneim-Forsch/Drug Research36(1, Nr. 5):781-892 (1986) found that the absorption site forgabapentin was the duodenum. The absorption of gabapentin occursrelatively slowly with the peak plasma concentration occurringapproximately 2-6 hours after dosing (Bourgeois, supra). The eliminationof gabapentin is exclusively through renal pathways (Chadwick; TheLancet 34 3:89-91 (1994); Vollmer, supra; Thomson, et al., Clin.Pharmacokinet. 23(3):216-230 (1992); and Riva, et al., Clin.Pharmacokinet. 31(6):470-493 (1996)) with reported half-lives of 5-7hours (Chadwick, supra) and 6-7 hours (Gram, supra).

A once- or twice-daily dosage form of gabapentin would be expected toimprove compliance and therefore a controlled release dosage form hassome distinct advantages over the conventional immediate releaseformulations. In addition, a controlled release dosage form would lowerthe maximum plasma concentration, and this may result in reduced sideeffects. Since gabapentin is absorbed high in the gastrointestinaltract, by means of a saturable transport mechanism, a gastric retaineddosage form is particularly beneficial for delivery of gabapentin sincethe dosage form would be able to keep the drug in the region ofabsorption and show improved bioavailability by virtue of the slowerrelease rate that avoids saturation of the carrier mediated transport ofconventional dosages.

Osmotic dosage forms have been described for delivery of gabapentinprodrugs. U.S. Pat. No. 6,683,112 to Chen et al. describes sustainedrelease formulations that deliver gabapentin prodrugs by means of thepush-pull osmotic pump system described in U.S. Pat. No. 4,612,008 toWong et al. This system however, is not a gastric retained dosage formand would be expected to deliver the drug with poor bioavailability.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a method of treating epilepsycomprising administering a therapeutically effective amount ofgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage fowl to a mammal in need of such treatment.

Yet another aspect of the invention relates to a method of treatingneuropathic pain comprising administering a therapeutically effectiveamount of gabapentin or a pharmaceutically acceptable salt thereof; in agastric retained dosage form to a mammal in need of such treatment.

Still another aspect of the invention relates to an improved method ofadministering a therapeutically effective amount of gabapentin to apatient in need thereof; the improvement comprising administeringgabapentin or a pharmaceutically acceptable salt thereof; in a gastricretained dosage form.

Yet another aspect of the invention pertains to an extended release oraldrug dosage form for releasing gabapentin into the stomach, duodenum andsmall intestine of the mammal, comprising a core comprising at least 800mg of gabapentin, surrounded by a semipermeable membrane or coating,which can be porous or non-porous.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the dissolution profiles for three GR™ formulations.

FIG. 2 illustrates the average plasma profile of three GR™ formulationsand Neurontin®.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a method of treating a disease state, such asepilepsy, by administering gabapentin in a once- or twice-daily gastricretained dosage form. The gastric retained dosage form is particularlybeneficial for delivery of gabapentin due to its prolonged transit inthe upper gastrointestinal tract, which allows the drug to be absorbedadequately in the preferred region of absorption. In addition, a gastricretained dosage form increases the t_(max), and allows for a smoother,more prolonged anti-spasmolytic effect. This dosage form also lowers theC_(max) and may result in reduced incidence and/or severity of CNS sideeffects of the drug, such as somnolence, ataxia, fatigue and dizziness.

A. Method of Treatment

The instant invention is a method of treating a disease state comprisingadministering a therapeutically effective amount of gabapentin, or apharmaceutically acceptable salt thereof, once- or twice-daily in agastric retained dosage form to a mammal in need of such treatment. Asused herein, the term “treating” covers treating the specified diseasein a mammal, particularly a human, and includes: (i) preventing thedisease from occurring in a subject which may be predisposed to thedisease but has not yet been diagnosed as having it; (ii) inhibiting thedisease, i.e. arresting its development; or (iii) relieving the disease,i.e. causing regression of the disease.

One embodiment of the invention relates to an improved method ofadministering a therapeutically effective amount of gabapentin to apatient in need thereof, the improvement comprising administeringgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form.

Other embodiments of the invention relate to methods of treatingspecific disease states comprising administering a therapeuticallyeffective amount of gabapentin or a pharmaceutically acceptable saltthereof, in a gastric retained dosage form to a mammal in need of suchtreatment. Such methods find utility in treating numerous disease statesthat are currently being treated with conventional immediate releaseformulations of gabapentin and include, by way of illustration and notlimitation, epilepsy; neuropathic pain; psychiatric disorders such asbipolar disorder and panic disorder; movement disorders such as restlessleg syndrome, periodic movement disorder of sleep, essential tremor andacquired nystagmus; and prophylaxis of migraine headaches.

The invention also contemplates administering one or more additionaltherapeutic agents with the gabapentin treatment. The selection of theseadditional therapeutic agents will depend upon the specific diseasestate being treated, and are described in detail below.

B. Active Ingredient

The active ingredient in the method of the invention is gabapentin.Gabapentin is preferably used in the free amphoteric form.Pharmaceutically acceptable salt forms that retain the biologicaleffectiveness and properties of gabapentin and are not biologically orotherwise undesirable can also be used and may show superiorbioavailability. As used herein, the term “gabapentin” is intended toinclude the agent itself, as well as its pharmaceutically acceptablesalts.

Pharmaceutically acceptable salts may be amphoteric and may be presentin the form of internal salts. Gabapentin may form acid addition saltsand salts with bases. Exemplary acids that can be used to form suchsalts include, by way of example and not limitation, mineral acids suchas hydrochloric, hydrobromic, sulfuric or phosphoric acid or organicacids such as organic sulfonic acids and organic carboxylic acids. Saltsformed with inorganic bases include, for example, the sodium, potassium,lithium, ammonium, calcium, and magnesium salts. Salts derived fromorganic bases include, for example, the salts of primary, secondary andtertiary amines, substituted amines including naturally-occurringsubstituted amines, and cyclic amines, including isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethyl aminoethanol, tromethamine, lysine, arginine,histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, fumarate, maleate, succinate,acetate and oxalate.

C. Additional Therapeutic Agents

The methods of the invention also contemplate the addition of one ormore therapeutic agents with the gabapentin treatment.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat epilepsy, such additionaltherapeutic agents can be other anti-epileptics or anticonvulsants,which include, by way of illustration and not limitation, hydantoins,iminostilbenes, valproates, phenyltriazines, barbiturates,deoxybarbiturates, benzodiazepines and carbamates. Such additionalagents are preferably hydantoins, iminostilbenes, valproates orphenyltriazines.

The following examples of compounds within each of these classes isintended to be illustrative and not limiting in any manner. Examples ofsuitable hydantoin anticonvulsants include ethotoin, fosphenytoin,mephenytoin, and, preferably, phenytoin. An examples of a suitableiminostilbene is carbamazepine. Examples of suitable valproates includevalprioic acid and sodium valproate. An exemplary suitablephenyltriazine is lamotrigene. A suitable barbiturate is phenobarbitaland an exemplary deoxybarbiturate is primidone. An example of a suitablebenzodiazepine is clorazepate. A suitable carbamate is felbamate.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat neuropathic pain, suchadditional therapeutic agents can be selected from the group consistingof other anticonvulsants, tricyclic antidepressants, levadopa, andopioids.

The following examples of compounds within each of these classes isintended to be illustrative and not limiting in any manner. Examples ofsuitable anticonvulsants include carbamazepine, phenytoin andlamotrigine. Suitable tricyclic antidepressants include amitriptyline,imipramine, clomipramine and desipramine. Examples of suitable opioidsinclude oxycodone and tramadol.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat psychiatric disorders,such additional therapeutic agents can be selected from the groupconsisting of lithium, carbamazepine, valproate, trifluoperazine,clonazepam, risperidone, lorazepam, venlafaxine, clozapine, olanzapine,benzodiazepines, neuroleptics, tricyclic antidepressants, selectiveserotonin reuptake inhibitor (SSRI's), buprupion, and nefadone.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat bipolar disorder, suchadditional therapeutic agents can be selected from the group consistingof lithium, carbamazepine, valproate, trifluoperazine, clonazepam,risperidone, lorazepam, venlafaxine, clozapine, olanzapine,benzodiazepines, and neuroleptics.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat depression, suchadditional therapeutic agents can be selected from the group consistingof tri-cyclic anti-depressants, SSRI's, bupropion, venlaxatine, andnefadone.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat manic disorders, suchadditional therapeutic agents can be selected from the group consistingof diazepam, and oxazepam.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat movement disorders, suchadditional therapeutic agents can be selected from the group consistingof benzodiazepines, dopaminergic agents, and opiates, particularlylevodopa/carbidopa and clonazepam.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered for prophylactic treatment ofmigraine headaches, such additional therapeutic agents can be selectedfrom the group consisting of tricyclic antidepressants (amitriptyline,doxepin, imipramine, maprotiline, protriptyline, desipramine), SSRI(fluoxetine), triptan (sumatriptan, etc.), and ergotamine.

D. Dosage

In general, the term “therapeutically effective amount” refers to thatamount which is sufficient to effect treatment, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending on the subject being treated, the severity of thedisease state and the manner of administration, and may be determinedroutinely by one of ordinary skill in the art.

In particular, for use in the treatment of epilepsy or neuropathic painwith a gastric retained dosage form, gabapentin may be used at dosesappropriate for treating epilepsy or neuropathic pain with immediaterelease dosage forms. However, the gastric retained dosage form isdesigned to provide for bioavailability of gabapentin at a level greaterthan or equal to 80% (>80%) relative to an equal dose of an immediaterelease dosage form. Typically, the method of the invention will involveadministering gabapentin on a once- or twice-daily basis for as long asthe condition persists.

An effective dosage of gabapentin for the treatment of epilepsy istypically in the range of about 300-3600 mg/day, typically about900-2400 mg/day, more typically about 900-1800 mg/day.

An effective dosage of gabapentin for the treatment of neuropathic painis typically in the range of about 100-4800 mg/day, typically about300-3600 mg/day, more typically about 900-2400 mg/day.

An effective dosage of gabapentin for the treatment of psychiatricdisorders is typically in the range of about 100-4800 mg/day, moretypically about 900-3600 mg/day.

An effective dosage of gabapentin for the treatment of movementdisorders is typically in the range of about 100-4000 mg/day, typicallyabout 200-2700 mg/day, more typically about 500-2700 mg/day.

An effective dosage of gabapentin for the prophylactic treatment ofmigraine headaches is typically in the range of about 200-4000 mg/day,typically about 500-3600 mg/day, more typically about 900-2400 mg/day.

E. Dosage Regimen

The methods of the invention provide a once- or twice-daily dose of thegabapentin gastric retained dosage form. The dosage can be administeredat any time, but it is preferred that the dosage is administered at thesame approximate time each day and in approximately 12 hour intervalsfor the duration of treatment. In addition, it is preferred that thegastric retained dosage form be taken with food, for example with themorning or evening meals.

Accordingly, in one embodiment of the invention, gabapentin isadministered once-daily, for example, in the morning (e.g., upon risingor with the morning meal) or in the evening (e.g., with the evening mealor near bedtime).

In another embodiment of the invention, gabapentin is administeredtwice-daily, for example, with the first dose being in the morning(e.g., upon rising or with the morning meal) and the second dose beingin the evening (e.g., with the evening meal or near bedtime).

In another aspect of the invention, the method of administering atherapeutically effective amount of gabapentin in a gastric retaineddosage form further includes administering one or more additionaltherapeutic agents.

The additional therapeutic agents can be administered at the same timeor at a different time than the administration of gabapentin, and willdepend upon the nature of the disease being treated as well as the agentitself. For example, when the additional agent is anotheranti-epileptic, a twice-daily dose is sufficient and it may beadministered at the same time or at a different time than gabapentin.For purposes of facilitating patient compliance, administration of anyof the aforementioned additional agents at the same time is preferred.

F. Dosage Form

There are several drug delivery systems that are suitable for use indelivering gabapentin in the method of the invention as they areparticularly tailored to be gastric-retained dosages, such as theswellable bilayer described by Franz, et al., U.S. Pat. No. 5,232,704;the multi-layer tablet with a band described by Wong, et al., U.S. Pat.No. 6,120,803; the membrane sac and gas generating agent described inSinnreich, U.S. Pat. No. 4,996,058; the swellable, hydrophilic polymersystem described in Shell, et al., U.S. Pat. No. 5,972,389 and Shell, etal., WO 9855107; all of which are incorporated herein by reference.

Of particular interest are gastric retained dosage forms that containhydrophilic polymers that swell to a size such that the dosage form isretained in the fed mode. For example, the gastric retained dosage formcan contain polymers with a high swelling capacity such as polyethyleneoxide, hydroxyethylcellulose and hydroxypropylmethylcellulose. Thepolymers are preferably of a moderate to high molecular weight (4×10³ togreater that 10⁷) to enhance swelling and provide control of the releaseof gabapentin. In one embodiment of the invention, ahydroxypropylmethylcellulose polymer of such molecular weight isutilized so that the viscosity of a 1% aqueous solution is about 4000cps to greater than 100,000 cps. An example of suitable polyethyleneoxide polymers are those having molecular weights (viscosity average) onthe order of 2-7 million. A typical dosage form should swell toapproximately 115% of its original volume within one hour afteradministration, and at a later time should swell to a volume that is130% or more of the original volume. Fillers, hinders, lubricants andother additives may also be included in the gastric retained dosageform, such as are well known to those of skill in the art.

A typical dosage form would provide for a drug delivery profile suchthat gabapentin both on an in vivo and in vitro basis, is delivered forat least 5 hours, and typically over a time period of about 8-10 hours.In order to provide for sustained delivery, it is preferable that atleast 40 wt % of gabapentin is retained in the dosage form after 1 hour,i.e., no more than 60 wt % of the drug is administered in the firsthour. In addition, it may be desired to utilize a dosage form thatprovides for substantially all of the gabapentin to be delivered overthe intended duration, which is typically about 6-12 hours, wheresubstantially all is taken to mean at least about 85 wt % of thegabapentin is administered.

In one embodiment of the invention, the gastric retained dosage form ofgabapentin is a capsule dosage form that allows for the extended releaseof gabapentin in the stomach and comprises: (a) at least one componentthat expands on contact with gastric juice and contains an agent capableof releasing carbon dioxide or nitrogen, gabapentin or apharmaceutically acceptable salt thereof; (b) at least one hydrophilicmembrane in the form of a sachet which contains component (a), expandsby inflation, floats on the aqueous phase in the stomach and ispermeable to gastric juice and; (c) capsule dosage form which containscomponents (a) and (b) and which disintegrates without delay in thestomach under the action of gastric juice. Component (a) may alsocontain a pharmaceutically acceptable hydrophilic swelling agent such aslower alkyl ethers of cellulose, starches, water-soluble aliphatic orcyclic poly-N-vinylamides, polyvinyl alcohols, polyacrylates,polymethacrylates, polyethylene glycols and mixtures thereof, as well asother materials used in the manufacture of pharmaceutical dosage forms.Further details regarding an example of this type of dosage form can befound in Sinnreich, U.S. Pat. No. 4,996,058.

In another embodiment of the invention, the gastric retained dosage formof gabapentin is an extended release oral drug dosage form for releasinggabapentin into the stomach, duodenum and small intestine of a patient,and comprises: a single or a plurality of solid particles consisting ofgabapentin or a pharmaceutically acceptable salt thereof dispersedwithin a polymer that (i) swells unrestrained dimensionally by imbibingwater from gastric fluid to increase the size of the particles topromote gastric retention in the stomach of the patient in which the fedmode has been induced; (ii) gradually the gabapentin diffuses or thepolymer erodes over a time period of hours, where the diffusion orerosion commences upon contact with the gastric fluid; and (iii)releases gabapentin to the stomach, duodenum and small intestine of thepatient, as a result of the diffusion or polymeric erosion at a ratecorresponding to the time period. Exemplary polymers includepolyethylene oxides, alkyl substituted cellulose materials andcombinations thereof, for example, high molecular weight polyethyleneoxides and high molecular weight or viscosityhydroxypropylmethylcellulose materials. Further details regarding anexample of this type of dosage form can be found in Shell, et al., U.S.Pat. No. 5,972,389 and Shell, et al., WO 9855107.

In yet another embodiment, a bi-layer tablet releases gabapentin to theupper gastrointestinal tract from an active containing layer, while theother layer is a swelling or floating layer. Details of this dosage maybe found in Franz, et al., U.S. Pat. No. 5,232,704. This dosage form maybe surrounded by a band of insoluble material as described by Wong, etal., U.S. Pat. No. 6,120,803.

Another embodiment of the invention uses a gastric retained swellable,sustained-release tablet having a matrix comprised of poly(ethyleneoxide) and hydroxypropylmethylcellulose. This dosage form is illustratedin Example 1 and further details may be found in Gusler, et al., U.S.Patent Application Publication No. 20030104053.

Yet another embodiment of the invention relates to a dosage form that isformulated to have a large enough size so as to provide for prolongedtransit in the upper gastrointestinal tract. Such tablets would containat least 800 mg of gabapentin, typically 800-1600 mg. Typically such adosage form will be a film coated dosage form or a capsule dosage formthat allows for the controlled and extended release of gabapentin in thestomach. In a preferred embodiment, the dosage form is a drug-containingcore surrounded by a controlled release film coating that provides forcontrolled or sustained drug release, i.e., continuous diffusion of drugfrom the core into the upper gastrointestinal tract.

Numerous materials useful for manufacturing these large-sized dosageforms are described in Remington: The Science and Practice of Pharmacy,20^(th) edition (Lippincott Williams & Wilkins, 2000) and Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, 6^(th) Ed.(Media, Pa.: Williams & Wilkins, 1995). Along with gabapentin, the coremay contain pharmaceutically acceptable additives or excipients tofacilitate manufacturing. These include binders (e.g., ethyl cellulose,gelatin, gums, polyethylene glycol, polyvinylpyrrolidone,polyvinylalcohol, starch, sugars, waxes), coloring agents, diluents(e.g., calcium sulfate, cellulose, dicalcium phosphate, kaolin, lactose,mannitol, microcrystalline cellulose, sodium chloride, sorbitol, starch,sucrose), flavoring agents, glidants (e.g., colloidal silicon dioxide,talc), and lubricants (e.g., calcium stearate, glyceryl behenate,hydrogenated vegetable oils, magnesium stearate, polyethylene glycol,sodium stearyl fumarate, stearic acid, stearyl behenate, talc). The coremay also contain pharmaceutically acceptable additives or excipientsthat serve to provide desirable physical characteristics to the dosageform. These include sweeteners, polymers, waxes and solubility-retardingmaterials. These dosage forms can be made by techniques that are wellestablished in the art, including wet granulation, fluid-bedgranulation, dry granulation, direct compression, and so forth.

The controlled release film coating can also be applied by techniquesthat are well established in the art, for example, by dissolving thematerial in an appropriate solvent such as acetone or methylene chlorideand is then applying the coating to the dosage form core by molding, airspraying, dipping or brushing a solvent-based solution of the materialonto the core. Materials suitable for use in controlled release filmcoatings include by way of illustration, and not limitation, mixtures ofwaxes such as beeswax and carnuba wax, shellac and zein, celluloses suchas ethyl cellulose, acrylic resins, cellulose acetates includingdiacetates and triacetates and other cellulose esters, and siliconeelastomers. Additional examples are set forth below.

Of particular interest are controlled release film coating materialsthat can form a semipermeable membrane or coating, which can be porousor non-porous, and which are permeable to external fluid, andsubstantially impermeable to the unsolubilized drug contained within thecore. Typically, external fluids are aqueous fluids or biological fluidsin the environment of use, such as the upper gastrointestinal tract.External fluid passes through the semipermeable membrane into the core,where it solubilizes the drug. The solubilized drug then moves from thecore through the membrane into the gastrointestinal tract.

After application of the controlled release film coating to the core, adrying step is required and then, a suitable exit means for thegabapentin must be formed through the semipermeable membrane. Dependingon the properties of the gabapentin and other ingredients within theinternal compartment and the desired release rate for the dosage form,one or more orifices for gabapentin delivery can be formed through themembrane by mechanical drilling, laser drilling, or the like. Theorifice(s) may range in size from a single large orifice containingsubstantially an entire surface of the dosage form to one or more smallorifices selectively located on the surface of the semipermeablemembrane. One specific embodiment of a semipermeable membrane-coatedcore is the elementary osmotic pump. The membrane is provided with oneor more delivery orifices, e.g., pierced with a laser to create one ormore delivery orifices. Fluid passing through the membrane into thecore, generates an osmotic pressure that serves to “pump” thesolubilized dug through the delivery orifice(s). See for example, U.S.Pat. No. 3,845,770 to Theeuwes et al. and U.S. Pat. No. 3,977,404 toTheeuwes.

The materials used in forming the semipermeable membrane can besubstantially insoluble in the external fluid or they can erode after apredetermined period of time with erosion taking place at the end of thegabapentin release period. Suitable materials include, by way ofillustration and not limitation: acetaldehyde dimethyl acetate andacetaldehyde dimethylcellulose acetate; agar acetate; alkylene oxide andalkyl glycidyl ether copolymers; amylose triacetate; beta glucan acetateand beta glucan triacetate; cellulosic materials, which includecellulose esters (e.g., mono-, di- and tricellulose acetates, celluloseacetate butyl sulfonate, cellulose acetate butyrate, cellulose acetatechloroacetate, cellulose acetate dimethylaminoacetate, cellulose acetateethyl carbamate, cellulose acetate ethyl carbonate, cellulose acetateethyl oxalate, cellulose acetate laurate, cellulose acetate methylcarbamate, cellulose acetate methyl sulfonate, cellulose acetate octate,cellulose acetate phthalate, cellulose acetate propionate, celluloseacetate succinate, cellulose acetate p-toluene sulfonate, celluloseacetate valerate, cellulose propionate, cellulose propionate succinate,dimethyl cellulose acetate, mono-, di- and tricellulose acrylates,mono-, di- and tricellulose alkanylates, mono, di and tricellulosearoylates, cellulose triacylates such as cellulose trilaurate, cellulosetripalmitate, cellulose trisuccinate and cellulose trivalerate, andcellulose diacylates such as cellulose dicaprylate, cellulosedioctanoate, cellulose dipalmatate, cellulose dipentanlate and cellulosedisuccinate), cellulose ethers (e.g., ethyl cellulose,hydroxyethylcellulose, hydroxypropylcellulose, and methylcellulose),cellulose ester-ether polymers, mono-, di- and tricellulose acrylates,mono-, di- and tricellulose alkenylates; hydroxylated ethylene-vinylacetate; perm-selective aromatic nitrogen containing polymeric membranesthat exhibit water permeability and essentially no solute permeability;polyamides; polyalkylene oxides such as crosslinked and non-crosslinkedpolyethylene oxide; polyether and polyamide copolymers; polyglycolicacid and polylactic acid and derivatives thereof; polymeric epoxides;poly(methacrylate) copolymer salts such as poly(ammonium methacrylate)copolymer, poly(aminoalkyl methacrylate) copolymer, and (ethylacrylate)-(methyl methacrylate)-[(trimethylammonium)-ethylmethacrylate](1:2:0.2) copolymer; cross-linked poly(sodium styrene sulfonate);crosslinked polystyrenes; polyurethanes; polyvinyl alcohol; crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); polyvinyl chloride;poly(vinylmethyl ether) copolymers; polyvinylpyrrolidone;propylcarbamate; sulfonated polystyrenes; triacetate of locust gum bean;and so forth; and combinations thereof.

Preferred materials for use in forming the semipermeable membrane,include, by way of illustration and not limitation: cellulose esters,cellulose ethers, polyvinylpyrrolidone, polyvinyl alcohol, polyalkyleneoxides, and combinations thereof.

The semipermeable membrane may also include one or more plasticizers,including: acetylated monoglycerides; dibutyl phthalate, diethylphthalate, isopropyl phthalate, dimethyl phthalate, and dactylphthalate; dibutyl sebacate and dimethyl sebacate; esters such as acetyltriethyl citrate, acetyl tributyl citrate, citrate ester, dibutylsebacate, tetraethyl acetate, triethyl citrate and other citrate esters;fatty acids such as stearic acid; glyceryl behenate; glycols such as1,2-butylene glycol, 2,3-butylene glycol, diethylene glycol, ethyleneglycol, propylene glycol, tetraethylene glycol, triethylene glycol andpolyalkyleneglycols such as polyethyleneglycol; oils such as castor oiland fractionated coconut oil; glycerin; glycerol and glycerolmonostearate; triacetin; and so forth; and combinations thereof

Preferred plasticizers include esters and fatty acids.

A particularly well-suited example of a core/coating system that can beused with gabapentin to provide for a gastric retained dosage form isthe delayed release tablet described in U.S. Pat. No. 6,350,471 to Seth,which comprises a drug/excipient core and a coating of awater-insoluble, water-permeable film-forming polymer such as ethylcellulose, a plasticizer such as stearic acid, and a water-solublepolymer such as polyvinylpyrrolidone or hydroxypropylcellulose.

Another suitable core/coating system has a polyvinyl alcohol coating,which is either a water soluble polyvinyl alcohol blended with a waterinsoluble polyvinyl alcohol, or a polyvinyl alcohol that has beencrosslinked with a material such as boric acid or sodium borate. Such acoating may also include one or more plasticizers.

For those embodiments of the invention that include furtheradministering additional therapeutic agents simultaneously withgabapentin, these agents can either be administered in the gastricretained dosage form that includes gabapentin or can be administered ina dosage form that is separate from gabapentin. Exemplary dosage formsare described below.

G. Dosage Form of Additional Agents

For those embodiments of the invention that include furtheradministering one or more additional therapeutic agents, such dosagescan be any suitable formulation as are well known in the art. For thoseadditional agents where controlled release is desirable, the agent maybe incorporated in the gabapentin gastric retained dosage form or beadministered in a separate gastric retained or other controlled releaseformulation dosage form. For those additional agents where immediaterelease is desirable, the agent may be incorporated in a coating aroundthe gabapentin gastric retained dosage form or in a separate layer of abilayer tablet, the agent may be simply enclosed in the capsule of theaforementioned gabapentin gastric retained capsule dosage form, or theagent may be administered in a separate immediate release dosage form.

Typically, dosage forms contain the additional agent (anotheranti-epileptic or anticonvulsant agent) in combination with one or morepharmaceutically acceptable ingredients. The carrier may be in the formof a solid, semi-solid or liquid diluent, or a capsule. Usually theamount of active agent is about 0.1-95 wt %, more typically about 1-50wt %. Actual methods of preparing such dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18thEdition, 1990. The dosage form to be administered will, in any event,contain a quantity of the additional therapeutic agent(s) in an amounteffective to alleviate the symptoms of the subject being treated.

In the preparation of pharmaceutical formulations containing theadditional therapeutic agent in the form of dosage units for oraladministration the agent may be mixed with solid, powdered ingredients,such as lactose, microcrystalline cellulose, maltodextrin, saccharose,sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin,or another suitable ingredient, as well as with disintegrating agentsand lubricating agents such as magnesium stearate, calcium stearate,sodium stearyl fumarate and polyethylene glycol waxes. The mixture isthen processed into granules or pressed into tablets such as chewableand oral disintegrating tablets.

Soft gelatin capsules may be prepared by mixing the active agent andvegetable oil, fat, or other suitable vehicle. Hard gelatin capsules maycontain granules of the active agent, alone or in combination with solidpowdered ingredients such as lactose, saccharose, sorbitol, mannitol,potato starch, corn starch, amylopectin, cellulose derivatives orgelatin.

Liquid preparations for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions containing about0.2-20 wt % of the active agent and the remainder consisting of sugar orsugar alcohols and a mixture of ethanol, water, glycerol, propyleneglycol and polyethylene glycol. If desired, such liquid preparations maycontain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations for oraladministration may also be prepared in the form of a dry powder to bereconstituted with a suitable solvent prior to use.

When the method of the invention includes administering anotheranti-epileptic or an anticonvulsant agent, there are numerouscommercially available dosage forms that can be administered. Inaddition, other formulations can be readily designed based uponknowledge in the art, and include the gastric-retained delivery systemsdescribed above.

Typical dosage forms of the other anti-epileptics or anticonvulsantssuitable for use in the invention include tablets, capsules, oralsuspensions and syrup. One of skill in the art can readily prepare oneof these exemplary formulations or the other anti-epileptic can beadministered by means of one of the numerous commercially availableproducts, examples of which are provided below.

Commercially available hydantoin anticonvulsants include, for example,Peganone® (ethotoin, Abbott); Mesantoin® (mephenytoin, Sandoz); andDilantin® (phenytoin, Warner-Lambert).

Typical dosage forms of the antineuralgics suitable for use in theinvention include tablets, capsules and oral suspensions. One of skillin the art can readily prepare one of these exemplary formulations orthe antineuralgic can be administered by means of one of the numerouscommercially available products, examples of which are provided below.

Commercially available antineuralgics include, for example, Atretol®(carbamazepine, Elan).

Although specific examples of suitable anti-epileptic, anticonvulsantagent and antineuralgic formulations are described above, it isunderstood that the invention is not limited to those examples as thereare numerous other formulations that can be used to deliver the otheranti-epileptic or anticonvulsant agents.

The general methods of the invention are best understood with referenceto the following examples which are intended to enable those skilled inthe art to more clearly understand and to practice the presentinvention. These examples are not intended, nor are they to beconstrued, as limiting the scope of the invention, but are merelyillustrative and representative thereof.

EXAMPLES Example 1

Tablets were manufactured using a dry blend process, and hand made on aCarver ‘Auto C’ Press (Fred Carver, Inc., Indiana). The dry blendprocess consisted of blending all of the ingredients in a plastic bag,and compressing into a 1000 mg tablet (600 mg gabapentin dose) using a0.7086″×0.3937″ Mod Oval die (Natoli Engineering). The parameters forthe operation of the Carver ‘Auto C’ Press were as follows: 4000 lbs.force, 0 second dwell time (the setting on the Carver Press), and 100%pump speed.

Formulation Composition (wt %) Sample # Active PEO Coagulant MethocelK100M M. St. 1 60.0 39.0 0.0 1 2 60.0 24.3 14.7 1 3 60.0 0.0 39.0 1where: Active = gabapentin PEO Coagulant = poly(ethylene oxide), gradePolyOx Coagulant, NF FP grade, manufactured by Union Carbide/DowChemical Company Methocel K100M = hydroxypropylmethylcellulose, gradeMethocel K100M, premium, manufactured by Dow Chemical Company M. St. =magnesium stearate, NF, supplied by Spectrum Chemical Company

The dissolution was determined in USP apparatus 1 (40 mesh baskets), 100rpm, in deionized water. Samples, 5 ml at each time-point, were takenwithout media replacement at 1, 4 and 8 hours.

The resulting cumulative dissolution profile, based upon a theoreticalpercent active added to the formulations is presented in tabulated formbelow:

Time Theoretical (wt %) of Active Released (hours) Sample 1 Sample 2Sample 3 1 15.4 14.8 18.6 4 39.4 37.4 43.3 8 61.7 57.8 64.7

Example 2

Tablets were manufactured using a dry blend process, and hand made on aCarver ‘Auto C’ Press (Fred Carver, Inc., Indiana). The dry blendprocess consisted of blending all of the ingredients in a plastic bag,and compressing into a 600 mg tablet (300 mg gabapentin) using a0.6299″×0.3937″ Mod Oval die (Natoli Engineering). The parameters forthe operation of the Carver ‘Auto C’ Press were as follows: ˜2000-2500lbs. force, 0 second dwell time (the setting on the Carver Press), and100% pump speed.

Formulation Composition (wt %) Sample # Active PEO Coagulant MethocelK15M M. St. 4 50.0 24.5 24.50 1 where: Active = gabapentin PEO Coagulant= poly(ethylene oxide), grade PolyOx Coagulant, NF FP grade,manufactured by Union Carbide/Dow Chemical Company Methocel K15M =hydroxypropylmethylcellulose, grade Methocel K15M, premium, manufacturedby Dow Chemical Company M St. = magnesium stearate, NF, supplied bySpectrum Chemical Company

The dissolution was determined in USP apparatus 1 (40 mesh baskets), 100rpm, in deionized water. Samples, 5 ml at each time-point, were takenwithout media replacement at 1, 2, 4 and 8 hours.

The resulting cumulative dissolution profile, based upon a theoreticalpercent active added to the formulation is presented in tabulated formbelow:

Time Theoretical wt % of Active Released (hours) Sample 4 1 20.6 2 32.44 49.7 6 63.1 8 74.0 10 82.6

Example 3

Three Gastric Retentive (GR™) gabapentin formulas were manufacturedutilizing a standard granulation technique. The formulationsmanufactured are shown in tabulated form below.

Formulations for Clinical Trial Manufacture Gabapentin GR8, 300-mgGabapentin GR6, 300-mg Gabapentin GR8, 600-mg (GR8, 300-mg) (GR6,300-mg) (GR8, 600-mg) 44.76% Gabapentin 44.76% Gabapentin 61.11%Gabapentin 21.99% Methocel ® K15M, 16.46% Methocel ® K4M, 7.59%Methocel ® K15M, premium premium premium 21.99% Sentry ® PolyOx ® 21.99%Sentry ® PolyOx ® 27.09% Sentry ® PolyOx ® WSR Coagulant, NF FP WSR 303,NF FP WSR 303, NF FP 7.49% Avicel ® PH-101, NF 12.98% Avicel ® PH-101,NF 0.00% Avicel ® PH-101, NF 2.75% Methocel ® E5, prem. 2.75% Methocel ®E5, prem. 3.22% Methocel ® E5, prem. 1.00% Magnesium Stearate, NF 1.00%Magnesium Stearate, NF 1.00% Magnesium Stearate, NF 670-mg 670-mg 982-mg0.3937″ X 0.6299″ Mod Oval 0.3937″ X 0.6299″ Mod Oval 0.4062″ X 0.75″Mod Cap

Gabapentin was obtained from Plantex U.S.A. (Englewood Cliffs, N.J.).Methocel® brand hydroxypropyl methylcellulose (also known ashypromellose), and Sentry® PolyOx® brand polyethylene oxide wereobtained from Dow Chemical (Midland, Mich.). Methocel E5, premium is aUSP type 2910 hydroxypropyl methylcellulose with number averagemolecular weight of on the order of 6000-8000 and a viscosity of 5 cpsas a 2% aqueous solution at 20° C. Methocel® K4M and Methocel® KI5M areUSP type 2208 hydroxypropyl methylcellulose with viscosities of 4000 cpsand 15,000 cps, respectively, as a 2% aqueous solution at 20° C., andnumber average molecular weights on the order of 80,000 and 100,000,respectively. Sentry PolyOx® WSR 301, NF FP, Sentry® PolyOx® WSRCoagulant, NF FP and Sentry® PolyOx® WSR 303, NF FP haveviscosity-average molecular weights of approximately 4,000,000,5,000,000 and 7,000,000, respectively. Avicel PH-101, NF ismicrocrystalline cellulose supplied by FMC Corporation (Philadelphia,Pa.). Magnesium stearate, NF was supplied by Spectrum Quality Products(New Brunswick, N.J.).

The dissolution profiles, as determined by USP Apparatus I (100 rpm) inmodified simulated gastric fluid, for three prototypes GR™ formulationsare shown in FIG. 1.

Example 4

The pharmacokinetic profiles of the three formulations described inExample 3, administered as a 600-mg dose, were compared to Neurontin®immediate release 300-mg capsule in a randomized four-way cross-overexperiment involving 15 healthy volunteers. Each subject wasadministered treatment of 600-mg gabapentin as one of the three GR™formulations (1×600-mg tablet or 2×300-mg tablet) or Neurontin® capsules(2×300-mg) within 5 minutes of completing a high fat breakfast (FDAbreakfast). Plasma samples were taken up to 48 hours post-dose. FIG. 2illustrates the average plasma profile for the four treatmentsadministered, and the pharmacokinetic data are summarized in tabulatedform below.

Gabapentin Plasma Data - Average for 15 Subjects AUC_(inf) ^(#) C_(max)^(#) T_(max) Dosing (μg/ml)*hr) (μg/ml) (hours) Nerontin ®, 300-mg Mean46.65 4.72 3.93 2 x capsules % CV 19.0 20.2 15.1 GR6, 300-mg Mean 44.432.97 6.63 2 x tablets % CV 34.9 29.7 45.1 GR8, 300-mg Mean 41.84 3.105.63 2 x tablets % CV 34.4 26.2 34.9 GR8, 600-mg Mean 48.01 3.13 7.13 1x tablet % CV 26.8 18.7 42.2 ^(#)Geometric Mean and Geometric % CV arereported here

As demonstrated in FIG. 2 and in tabulated form above, GR™ formulationsdemonstrate sustained release with a lower maximum plasma concentrationand a larger value for the time of the maximum concentration compared tothe immediate release capsules without loss in the bioavailability asmeasured by the plasma AUC_(inf).

Example 5

A tablet containing 900 mg of gabapentin is prepared by granulation with90 mg of polyvinylpyrrolidone and 10 mg of magnesium stearate and thentableted as a 1000 mg tablet on a Carver press with 4000 lbs force, 0second dwell time. These tablet cores are then coated from analcohol-water solution that dries with approximately 2% dry coat weightof 10 mg ethyl cellulose, 7 mg Povidone (PVP), and 3 mg stearic acid.

Example 6

A tablet containing 1200 mg of gabapentin is prepared by granulationwith 120 mg of polyvinylpyrrolidone and 10 mg of magnesium stearate andthen tableted as a 1330 mg tablet on a Carver press with 4000 lbs force,0 second dwell time. These tablet cores are then coated from analcohol-water solution that dries with approximately 25 mg dry coatweight of 10 mg ethyl cellulose, 10 mg hydroxypropylcellulose, and 5 mgglyceryl behenate.

Example 7

A tablet containing 900 mg of gabapentin is prepared by granulation with90 mg of polyvinylpyrrolidone and 10 mg of magnesium stearate and thentableted as a 1000 mg tablet on a Carver press with 4000 lbs force, 0second dwell time. These tablet cores are then coated from an aqueoussolution that dries with approximately 2% dry coat weight of 15 mgpolyvinyl alcohol (PVA), 5 mg Povidone (PVP), and 3 mg stearic acid. Thecoated tablets are then sprayed with an aqueous solution of 1% sodiumborate to crosslink the PVA and dried.

Example 8

A tablet containing 900 mg of gabapentin is prepared by granulation with90 mg of polyvinylpyrrolidone, 250 mg microcrystalline cellulose, and 10mg of magnesium stearate and then tableted as a 1250 mg tablet on aCarver press with 4000 lbs force, 0 second dwell time. These tabletcores are then coated from an alcohol-water solution that dries withapproximately 2% dry coat weight of 10 mg ethyl cellulose, 7 mg Povidone(PVP), and 3 mg stearic acid.

Each of the patent applications, patents, publications, and otherpublished documents mentioned or referred to in this specification isherein incorporated by reference in its entirety, to the same extent asif each individual patent application, patent, publication, and otherpublished document was specifically and individually indicated to beincorporated by reference.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A method for treating epilepsy, psychiatric disorders, neuropathic pain or movement disorder, comprising administering an extended release oral dosage form comprising an osmotic device and gabapentin, wherein the oral dosage form is formulated to have a size large enough to provide prolonged transit in the upper gastrointestinal tract of a subject in the fed mode.
 2. The method according to claim 1, wherein the dosage form provides for bioavailability of gabapentin at a level greater than or equal to 80% of that provided by an equal dose of gabapentin released by the immediate release dosage form as measured by the plasma AUC_(inf).
 3. The method according to claim 2, wherein the gabapentin is released into the upper gastrointestinal tract over a period of about 5-12 hours at a rate sufficient to achieve a lower maximum plasma concentration (C_(max)) compared to an equal dose of gabapentin provided by an immediate release dosage form.
 4. The method according to claim 1, wherein the osmotic device comprises an elementary pump.
 5. The method according to claim 1, wherein the osmotic device comprises a macroporous membrane.
 6. The method according to claim 1, wherein the dosage form comprises about 100 mg to about 4800 mg gabapentin.
 7. The method according to claim 1, wherein the dosage form comprises about 300 mg or about 600 mg gabapentin.
 8. The method according to claim 1, wherein the dosage form further comprises a second therapeutic agent selected from the group consisting of a hydantoin, an iminostilbene, a valproate, a phenyltriazine, a barbiturate, a dexoybarbiturate, a benzodiazepine, a carbamate, an anticonvulsant other than gabapentin, a tricyclic antidepressant, levadopa, carbidopa, an opioid, lithium, carbamazepine, valproate, trifluoperazine, clonazepam, risperidone, lorazepam, venlafaxine, clozapine, olanzapine, a neuroleptic, a serotonin reuptake inhibitor, buproprion, nefadone, venlaxatine, nefadone, diazepam, oxazepam, a dopaminergic agent, clonazepam, a triptan and ergotamine.
 9. The method according to claim 1, wherein the osmotic device comprises a push-pull osmotic device comprising a first osmotic composition and a second osmotic composition housed in a compartment of the push-pull osmotic device.
 10. The method according to claim 9, wherein the gabapentin is released into the upper gastrointestinal tract over a period of about 5-12 hours at a rate sufficient to achieve a lower maximum plasma concentration (C_(max)) compared to an equal dose of gabapentin provided by an immediate release dosage form.
 11. The method according to claim 9, wherein the dosage form provides for bioavailability of gabapentin at a level greater than or equal to 80% of that provided by an equal dose of gabapentin released by the immediate release dosage form as measured by the plasma AUC_(inf).
 12. The method according to claim 9, wherein the dosage form comprises about 100 mg to about 4800 mg gabapentin.
 13. The method according to claim 9, wherein the dosage form comprises about 300 mg or about 600 mg gabapentin.
 14. The method according to claim 9, wherein the dosage form further comprises a second therapeutic agent selected from the group consisting of a hydantoin, an iminostilbene, a valproate, a phenyltriazine, a barbiturate, a dexoybarbiturate, a benzodiazepine, a carbamate, an anticonvulsant other than gabapentin, a tricyclic antidepressant, levadopa, carbidopa, an opioid, lithium, carbamazepine, valproate, trifluoperazine, clonazepam, risperidone, lorazepam, venlafaxine, clozapine, olanzapine, a neuroleptic, a serotonin reuptake inhibitor, buproprion, nefadone, venlaxatine, nefadone, diazepam, oxazepam, a dopaminergic agent, clonazepam, a triptan and ergotamine.
 15. A method for administering a therapeutically effective amount of gabapentin to a patient in need thereof comprising, administering an extended release oral dosage form comprising an osmotic device and gabapentin, wherein the oral dosage form is formulated to have a size large enough to provide prolonged transit in the upper gastrointestinal tract of a subject in the fed mode.
 16. The method according to claim 1, wherein the dosage form provides for bioavailability of gabapentin at a level greater than or equal to 80% of that provided by an equal dose of gabapentin released by the immediate release dosage form as measured by the plasma AUC_(inf).
 17. The method according to claim 2, wherein the gabapentin is released into the upper gastrointestinal tract over a period of about 5-12 hours at a rate sufficient to achieve a lower maximum plasma concentration (C_(max)) compared to an equal dose of gabapentin provided by an immediate release dosage form.
 18. The method according to claim 1, wherein the osmotic device comprises an elementary pump.
 19. The method according to claim 1, wherein the osmotic device comprises a macroporous membrane.
 20. The method according to claim 1, wherein the dosage form comprises about 300 mg to about 600 mg gabapentin. 